Pharmacologic Induction Of Estrus

It is clear that use of artificial lighting is the most successful and most widely employed method for jump-starting the breeding season. However, is there hope for a pharmacologic approach that does not require rewiring the farm? The short answer is that there is hope — but not necessarily promise.

Careful study of Table Physiologic Events of Vernal Transition in Chronologic Order reveals the problem to be surmounted in order for a mare to reinitiate estrous cyclicity. Luteinizing hormone (LH) secretion from the pituitary is, for all practical purposes, limiting throughout anestrus and vernal transition. These authors have shown that the gene for production of the LH subunits is not detectable in the pituitaries of anestrus mares. It is this reduction or outright lack of LH that appears to be responsible for the anovulatory vernal transition follicles. The reduction in pituitary LH appears to continue even after hypothalamic gonadotropin-releasing hormone (GnRH) secretion is renewed. That may explain the mixed results when GnRH is administered to mares in vernal transition in attempts to stimulate ovulation. Studies that employed this strategy several years ago were promising, but positive results likely reflected treatment given to mares further along in vernal transition. Similarly, studies using synthetic progestins to “stimulate” early onset of estrous cyclicity may have employed mares further along in vernal transition.

Dopamine Antagonist and Seasonality in Horses

In species such as sheep, evidence indicates that dopamine plays an inhibitory role on the hypothalamic-pituitary axis (HPA) during the nonbreeding season. Specifically, gonad-otropin secretion decreases during the nonbreeding season because of a neuronal inhibition of GnRH secretion via dopaminergic input. The inhibition of the HPA occurs only during anestrous and is estrogen-dependent.

Although a direct relationship between dopamine secretion and suppression of the equine HPA has not been demonstrated to date, dopamine concentrations in cerebrospinal fluid are highest in mares during anestrus. Thus recent interest in studying the effects of various dopamine antagonists on the equine hypothalamic-pituitary-gonadal axis and their subsequent effects on the timing of the breeding season in mares has been considerable.

The first dopamine antagonist to be tested was sulpiride at a dose of 0.5 mg/kg, orally every 12 hours. This dose caused a significant advance of the onset of the breeding season. Similarly, when domperidone (1.1 mg/kg once daily orally), another dopamine antagonist, was administered to horses during early vernal transition, it resulted in a significant advance of the onset of the breeding season over that in control mares. The primary difference between sulpiride and domperidone is that sulpiride crosses the blood-brain barrier, whereas domperidone does not.

The reported effect of dopamine antagonist on accelerating the onset of the breeding season in mares has been further evaluated to determine what effect, if any, the antagonist has on the hypothalamic-pituitary axis. Brendemuehl and Cross (2000) treated anestrous mares with domperidone beginning on January 15 and reported no effect on FSH, LH, nor estradiol secretion. However, Brendemuehl and Cross (see readings list) reported a significant advance in the onset of the breeding season in those mares treated with domperidone (51 days versus 130 days). Similarly, unpublished data from laboratory of the authors of this chapter reported that anestrous pony mares treated with sulpiride twice daily for 2 weeks during winter anestrus were not different from control mares with respect to LH and GnRH secretion. Therefore the data suggest that dopamine antagonist may accelerate the onset of the breeding season in vernal transition mares but not through activation of the hypothalamic-pituitary axis. Recent work by Daels and colleagues (2000) reported that treatment of anestrous mares with daily sulpiride plus extended photoperiod and ambient temperature resulted in an advance of the onset of the breeding season. However, when mares were treated with sulpiride alone and maintained under natural photoperiod and natural temperatures, no difference in date of the first ovulation of the year was found. It is important to note that no data on the fertility of the reported “early” ovulations exist.

Although the current evidence that suggests that dopamine antagonist may be helpful in manipulating the timing of the first ovulation of the year in mares is promising, variation in results may again suggest that treatment efficacy depends to some extent on the photic status of the mare. As in many experimental treatments, timing of treatment may be critical relative to photic exposure (anestrous versus vernal transition). These authors have proposed the idea of a “photic gate,” which means that some neural mechanism(s) require exposure to stimulatory photoperiods before pharmacologic initiation of estrous cyclicity can be accomplished.